Disorders causing visual impairment are numerous. Optic neuropathy is a medical disorder involving visual impairment related to optic nerve damage. The primary symptom of optic neuropathy is vision loss, which is generally bilateral, painless, gradual, and progressive. This vision loss often initially presents as a change in color vision, or dyschromatopsia, and also often begins with a centralized blurring, followed by a progressive decline in visual acuity. The vision loss from optic neuropathy can result in total blindness. Other clinical diagnoses frequently accompany optic neuropathy, including optic nerve head drusen, or accumulations of extracellular material on the optic nerve head, and/or papillitis, or inflammation of the optic nerve head.
There are many forms of optic neuropathy which are generally delineated based upon the cause of the neuropathy. One such form is toxic optic neuropathy, meaning nerve damage resulting from the presence of toxic compounds, such as methanol, ethylene glycol, ethambutol, or certain antibiotics. Another form of optic neuropathy is nutritional optic neuropathy, which is caused by certain nutritional deficiencies. The most common nutritional deficiencies that result in optic neuropathy are B-vitamin deficiencies, such as thiamine, niacin, riboflavin, or folic acid deficiency. (See, e.g., Glaser J S: Nutritional and toxic optic neuropathies. In: Glaser J S, ed., Neuro-ophthalmology. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 1999: 181-6; Lessell S: Nutritional deficiency and toxic optic neuropathies. In: Albert D M, Jakobiec F A, eds., Principles and Practice of Ophthalmology. 2nd ed. Philadelphia: W. B. Saunders Company; 2000: 4169-76; and Phillips P: Toxic and deficiency optic neuropathies. In: Miller N R, Newman N J, Walsh F B, Hoyt W F, eds., Walsh and Hoyt's Clinical Neuro-ophthalmology. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2005: 447-63). In cases of nutritional optic neuropathy, the treatment generally employed is to increase the intake of the deficient nutrient. For example, when the optic neuropathy is caused by folic acid deficiency, the disorder can be successfully treated by folic acid supplementation (see, e.g., P. de Silva, et al., Folic acid deficiency optic neuropathy: A case report, Journal of Medical Case Reports 2:299 (2008)).
Retinopathies are another common optic disorder. Retinopathies are disorders that present as non-inflammatory damage to the retina of the eye. Like neuropathies, retinopathies can have numerous causes and are frequently delineated based upon their cause, such as diabetic retinopathy, hypertensive retinopathy, and genetic retinopathy. (Wright, et al., Homocysteine, folates, and the eye, Eye (Land), August 2008, 22(8):989-93, available online Dec. 7, 2007; Abu El-Asrar, et al., Hyperhomocysteinemia and retinal vascular occlusive disease, Eur. J. Ophthalmol., November-December 2002, 12(6):495-500; Becker et al., Epidemiology of homocysteine as a risk factor in diabetes, Metab. Syndr. Relat. Disord., June 2003, 1(2)105-20; Faye A Fishman, The Gale Group Inc., Gale, Detroit, Gale Encyclopedia of Medicine, 2002).
Macular degeneration is yet another common optic disorder. Macular degeneration is an optic disorder characterized by vision loss due to damage to the center of the retina, or macula. This retinal damage is caused by damage to the blood vessels that supply that macula. To a large extent, it is unknown what ultimately causes this blood vessel damage that results in macular degeneration and there is no known treatment for macular degeneration at this time, though vitamin supplements have been suggested to slow the progression of macular degeneration. (Health News, B vitamins may be “silver bullet” for age-related macular degeneration: Daily supplementation with folic acid plus vitamins B6 and B12 may reduce risk of AMD by 35-40 percent, May 2009, 15(5):8-9; Mary Bekker, The Gale Group Inc., Gale, Detroit, Gale Encyclopedia of Nursing and Allied Health, 2002).
Dry Eye Syndrome is still another optic disorder. This disorder, also called Keratoconjunctivitis Sicca (KCS) or Keratitis Sicca, is caused by decreased tear production or increased tear film evaporation. This disorder is usually bilateral and is characterized by dryness and irritation of the eye, frequently getting worse as the day goes on. (“Keratoconjunctivitis Sicca” in The Merck Manual, Home Edition, Merck & Co., Inc., 2003, available at http://www.merck.com/mmhe/sec20/ch230/ch230d.html.).
Folate is a required nutrient and is frequently added to processed foods, such as cereals and breads, in the form of folic acid. However, folic acid is not itself a generally useful form of folate from a metabolic standpoint. Instead, folic acid is converted, through a series of enzymatic steps, to more metabolically active forms of folate via the folate cycle. In the folate cycle, folic acid is first converted into dihydrofolate (DHF) in the presence of vitamin B3. Also with the aid of vitamin B3, DHF is in turn converted into tetrahydrofolate (THF). THF is then converted into 5,10-methylenetetrahydrofolate (5,10-METHF), either directly or via 5-formiminotetrahydrofolate (5FITHF) and 5,10-methenyltetrahydrofolate intermediates. As a part of this same general process, 5-formyltetrahydrofolate (folinic acid), another folate compound, is also converted into 5,10-METHF, again via a 5,10-methenyltetrahydrofolate intermediate. Finally, 5,10-METHF is converted to 5-methyltetrahydrofolate (5MTHF), also called L-methylfolate, levomefolic acid, levomefolate, (6S)-5-methyltetrahydrofolate (6S-5MTHF), which is the predominant metabolically active form of folate. (Hasselwander et al., 5-Methyltetrahydofolate—the active form of folic acid, Functional Foods, 2000 Conference Proceedings, pp 48-59; Kelly et al., Unmetabolized folic acid in serum: acute studies in subjects consuming fortified food and supplements, Am. J. Clin. Nutr., 1997, 65:1790-95).
While this is the ideal path for metabolism of folic acid, as many as 50% of population may have a reduced ability to effectively convert folic acid into its useable form. (Klerk et al., MTHFR 677 C-T polymorphism and risk of coronary heart disease: A Meta-analysis, JAMA, 2002, 288:2023-30). Because of this, it is possible to have insufficient amounts of metabolically useful folate despite having adequate folic acid intake.
The folate cycle is not isolated, but rather interacts with, and in some cases is intertwined with, other metabolic cycles. For example, the folate cycle interacts with the methylation cycle (also known as the methionine cycle), which produces methionine from homocysteine. More specifically, 5MTHF produced by the folate cycle donates a methyl group which ultimately allows methionine to be produced from homocysteine. Additionally, the folate cycle interacts with the BH4 cycle, which produces tetrahydrobiopterin (BH4) from dihydrobiopterin (BH2). In this case, the interaction between the cycles involves both cycles utilizing a common enzyme: methylenetetrahydrofolatereductase (MTHFr). Because of these complex interactions, malfunctions in one cycle can cause subsequent malfunctions in the other, related cycles. For example, if an individual has a malfunction in the folate cycle such that insufficient 5MTHF is produced, this can cause a buildup of homocysteine and a deficiency of methionine due to an inability of that individual to use the former to produce the latter.
Vitamin B-12 is also intimately linked to the folate cycle. For instance, vitamin B-12 is an important cofactor in the metabolism of intermediate folate compounds, as well as being involved in multiple pathways that utilize L-methylfolate. One example of vitamin B-12's involvement in a pathway that involves L-methylfolate is again in the conversion of homocysteine into methionine. As stated above, 5MTHF donates a methyl group that eventually results in conversion of homocysteine into methionine. That methyl group is transferred from 5MTHF to cobalamin, an unmethylated form of vitamin B-12, thereby producing the methyl form of vitamin B-12, methylcobalamin (also called methyl-B12). Methylcobalamin in turn donates the methyl group to homocysteine to convert it into methionine. Thus, if an individual has an inadequate supply of vitamin B-12, the conversion of homocysteine to methionine will be negatively impacted. Vitamin B-12 is also important in other ways, such as being necessary for nerve repair and nerve health. Because of this, deficiencies in vitamin B-12 and methylcobalamin in particular, can lead to serious complications, such as pernicious anemia.
Because the cycles in which many of these nutrients are involved contain multiple enzymatic steps, they are prone to malfunction. Such malfunction can result, for example, from environmental toxins, ingested chemical compounds or toxins, metabolic imbalances, or genetic polymorphisms in the enzymes which carry out the process steps. For instance, the enzyme MTHFr is involved in the folate cycle. More specifically, this enzyme is at least partially responsible for converting 5,10-METHF into 5MTHF. Mutations in the portion of this enzyme that is involved in this conversion are known to exist. One such mutation, the C677T mutation, is known to slow down the folate cycle activity of this enzyme, resulting in reduced production of 5MTHF from its precursor product(s). For instance, individuals with this particular polymorphism have reduced CNS L-methylfolate. (Surtees et al., Association of cerebrospinal fluid deficiency of 5-methyltetrahydrofolate, but not S-adenosylmethionine, with reduced concentrations of the acid metabolites of 5-hydroxytryptamine and dopamine, Clinical Science, 1994, 86:697-702). Moreover, approximately 70% of patients with diabetic retinopathy have this genetic polymorphism. (Sun et al., The relationship between MTHFR gene polymorphisms, plasma homocysteine levels and diabetic retinopathy in type 2 diabetic meilitus, Chin. Med. J., 2003, 116 (1): 145-7).
MTHFr is also susceptible to mutation in those portions of the enzyme with activities outside the folate cycle. For instance, another function of MTHFr is the conversion of dihydrobiopterin (BH2) to tetrahydrobiopterin (BH4) in the BH4 cycle. BH4 is subsequently involved in multiple other biological pathways and is essential in the synthesis of numerous catecholamines (e.g., dopamine and noradrenaline/norepinephrine) and indolamines (e.g., serotonin and melatonin), as well nitric oxide synthases, which are involved in immune functions as well as vascularization. As such, a mutation in the portion of MTHFr responsible for BH4 cycle activity, such as the A1298C polymorphism, can cause a disruption in the BH4 pathway and subsequent malfunctions in numerous downstream pathways. For example, the A1298C polymorphism has been associated with glaucoma, with higher incidence of cardiovascular disease, and with incidence of eye disease, such as retinopathy. (Shazia et al., MTHFR and A1298C polymorphism and homocysteine levels in primary open angle and primary closed angle glaucoma, Molecular Vision, 2009, 15:2268-2278; Haviv et al., The common mutations C677T and A1298C in the human methylenetetrahydrofolate reductase gene are associated with hyperhomocysteinemia and cardiovascular disease in hemodialysis patients, Nephron, September 2002, 92(1):120-6; Targher et al., Diabetic retinopathy is associated with an increased incidence of cardiovascular events in Type 2 diabetic patients., Diabetic Medicine, 2008, 25:45-50).
Moreover, because these multiple cycles are intricately intertwined, a single malfunction can have far-reaching effects. Anything that breaks down the methylation cycles impacts nitric oxide levels, affects red blood cell function, increases inflammation, causes immune system malfunctions, causes detoxification system malfunctions, causes antioxidant system malfunctions, and negatively impacts our ability to heal and repair. The results of this are reduced blood flow and reduced red blood cells, both of which cause less nutrients and oxygen to get to the eyes; increased inflammation; and reduced detoxification. All of this has been linked to Diabetic retinopathy, Glaucoma, Dry Eyes, Age-related macular degeneration (AMD), branch retinal artery occlusion, a central retinal artery occlusion, a branch retinal vein occlusion, a central vein occlusion, optic neuropathy, and optic neuritis.
Because of the fortification of many processed foods, such as cereals and breads, with folic acid, excessive levels of folic acid may exist in much of the human population. For instance, the U.S. National Academy of Sciences recommends a daily intake of 150-600 .mu.g of folic acid depending on the individual's age and pregnancy status. Many folic acid fortified breakfast cereals supply this amount in a single serving, as do many daily multivitamins. In addition, fortified breads frequently supply 5-10% (or more) of the daily requirement in a single slice, while other fortified grains, such as rice, frequently supply 10-20% (or more) of the daily requirement in a single serving. Because of this, it is very common for an individual to have well over twice, and sometimes upwards of four times, the recommended daily intake of folic acid. (USDA National Nutrient Database for Standard Reference, Release 22, Content of Selected Foods per Common Measure, Folate, DFE sorted by nutrient content).
This is somewhat troubling given that it has been suggested that excessive levels of folic acid might be detrimental in several regards. For instance, some studies have suggested an antagonistic effect of excess folic acid on the metabolically active form by demonstrating an inverse relationship between the amount of unmetabolized folic acid in the blood and the ability of L-methylfolate to cross cell membranes. (Wollack et al., Characterization of folate uptake by choroid plexus epithelial cells in a rat primary culture model, J. Neurochem. 2008; 104:1494-1503; Reynolds, Benefits and risks of folic acid to the nervous system, J. Neurol. Neurosurg. Psychiatry, 2002, 72:567-71).
Further, unmetabolized folic acid has been linked to increased risk of cancer, growth of abnormal cells, increased depression, neurological complications, and decreased immune response. (Troem et al., Unmetabolized Folic Acid in Plasma Is Associated with Reduced Natural Killer Cell Cytotoxicity among Postmenopausal Women, J. Nutr., 2006, 136:189-194; Smith et al., Pteridines and mono-amines: relevance to neurological damage, Postgrad. Med. J., 1986, 62(724):113-23; Asien et al., High-dose B vitamin supplementation and cognitive decline in Alzheimer disease: a randomized controlled trial, JAMA, 2008, 300(15):1774-83). The presence of unmetabolized folic acid in the body has not heretofore been linked with pathological conditions of the eye. However, active folate and active vitamin B-12 have been found to improve corneal nerve fiber density (CNFD) and branch density, for example in patients with diabetic neuropathies. (Quattrini et al., Surrogate Markers of Small Fiber Damage in Human Diabetic Neuropathy, Diabetes, 2007, 56(8):2148-54).